We postulate that preclinical Alzheimer's disease (AD) is characterized by a long asymptomatic period in which the accumulation of cerebral lesions eventually results in dementia. To be truly effective, therapeutic interventions for AD may need to be initiated in this preclinical stage, prior to the occurrence of extensive and irreversible brain image. Because preclinical AD is asymptomatic, antecedent biological markers, neuroimaging measures, or other indicators need to be developed for its antemortem identification. In this application, we test the hypothesis that biomarkers and other indicators of the cerebral changes of preclinical AD can be detected in middle age individuals, particularly those who are at increased risk for AD. We will recruit, assess, and follow two groups of adult children: those with a biologic parent with dementia of the Alzheimer type (DAT) and those for whom neither parent has DAT. Four integrated projects, supported by Administration and Clinical Cores, will evaluate antecedent biomarkers in this Adult Children Study (ACS). Project 1 will compare cerebral binding of the amyloid imaging tracer, Pittsburgh Compound B, in the 2 groups of ACS participants. Project 2 will assay markers in blood and cerebrospinal fluid (including A?, tau, and sulfatide) and conduct proteomic studies to evaluate AD risk as a function of family history and apoE genotype. Project 3 will explore attentional performance profiles, within-subject performance variability, and personality dimensions as indicators of preclinical AD. Project 4 will use structural MRI to assess volume, shape, and thickness of selected brain regions as potential neuroanatomical markers of preclinical AD. Although we appreciate that this is a high risk, high reward application, we are fully committed to the successful completion of our aims and are uniquely positioned to do so: we have demonstrated the feasibility of enrolling the ACS cohort, have an interdisciplinary team of highly accomplished investigators with a long track record of productive collaboration, and are supported by the remarkable resources and infrastructure of the Alzheimer's Disease Research Center and a complementary Program project at Washington University.